Project Summary The United States is currently in an opioid crisis, and NIDA is committed to research on the mechanisms and treatment of opioid use disorder. Current Food and Drug Administration-approved pharmacotherapies for opioid use disorder include the MOR agonist methadone, the MOR partial agonist buprenorphine, and the MOR antagonist naltrexone. However, the clinical utility of all three compounds is limited for various reasons. Therefore, it is imperative to develop novel and effective drug candidates with enhanced therapeutic effects and reduced undesirable effects. Recently, we have identified several highly selective and potent MOR modulators as novel leads for opioid use disorder treatment. They all showed more promising pharmacological profiles compared to other known drugs in this category. The current proposal will focus on further development of these leads for preclinical IND-enabling studies, and dynamic drug discovery and development pipeline construct. Four integrated specific aims will be pursued in this project in two phases. In the UG3 phase, we will 1) further Validate therapeutic profiles of the current leads with self-administration and PK studies, and 2) expand the small molecule library to build a dynamic drug discovery and development pipeline. In the UH3 phase, we will 1) conduct preclinical IND-enabling studies on the lead(s) identified from UG3 phase, and 2) compare in vivo pharmacokinetics and pharmacodynamics profiles of the new hits from UG3 phase with current leads to define our next generation of lead compound(s).